Uremic Toxins Inhibit Transport by Breast Cancer Resistance Protein and Multidrug Resistance Protein 4 at Clinically Relevant Concentrations

Mutsaers, Henricus A M; Heuvel, Lambertus P. van den; Ringens, Lauke H. J.; Dankers, Anita C. A.; Rüssel, Frans G. M.; Wetzels, Jack F.M.; Hoenderop, Joost G. J.; Masereeuw, Rosalinde

doi:10.1371/journal.pone.0018438

Cited by 119 publications

(119 citation statements)

References 35 publications

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“…In this regard, it has been shown that PCG per se has no effect on leukocyte oxidative burst activity, whereas it may induce a synergistic activating effect in the presence of PCS (12). In addition, the effect of PCG on proximal tubular cells is equivocal (25,26). Additional research is required to elucidate the relevance of a decrease in sulfotransferase activity in patients with advanced CKD with respect to phase 2 metabolism of p-cresol and possibly, also endogenous and drug metabolism in general.…”

Section: Discussionmentioning

confidence: 99%

Metabolism, Protein Binding, and Renal Clearance of Microbiota–Derived p-Cresol in Patients with CKD

Poesen

Evenepoel

Loor

et al. 2016

CJASN

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Background and objectives Colonic microbial metabolism substantially contributes to uremic retention solutes in CKD. p-Cresyl sulfate is the main representative of this group of solutes, relating to adverse outcomes. Other than sulfate conjugation, p-cresol is subjected to endogenous glucuronide conjugation. Whether the balance between sulfate and glucuronide conjugation is relevant in CKD is unexplored.Design, setting, participants, & measurements We prospectively followed 488 patients with CKD stages 1-5 (enrollment between November of 2005 and September of 2006; follow-up until December of 2010). Serum and urine levels of p-cresyl sulfate and p-cresyl glucuronide were measured using liquid chromatography-mass spectrometry. Total amount of microbial p-cresol was calculated by the sum of serum p-cresyl sulfate and p-cresyl glucuronide. Outcome analysis was performed for mortality and cardiovascular disease.Results Serum p-cresyl sulfate was a median of 193.0-fold (interquartile range, 121.1-296.6) higher than serum p-cresyl glucuronide, with a significant correlation between eGFR and proportion of serum p-cresyl sulfate to glucuronide (rho=0.23; P=0.001). There was also a significant correlation between eGFR and proportion of 24-hour urinary excretion of p-cresyl sulfate to glucuronide (rho=0.32; P,0.001). Higher serum p-cresol and lower proportion of serum p-cresyl sulfate to glucuronide were jointly and significantly associated with mortality (hazard ratio per SD higher, 1.58; 95% confidence interval, 1.10 to 2.29; P=0.01 and hazard ratio, 0.65; 95% confidence interval, 0.47 to 0.89; P,0.01, respectively) and cardiovascular disease (hazard ratio, 1.68; 95% confidence interval, 1.27 to 2.22; P,0.001 and hazard ratio, 0.55; 95% confidence interval, 0.42 to 0.72; P,0.001, respectively) after adjustment for eGFR, Framingham risk factors, mineral bone metabolism markers, C-reactive protein, and albumin.Conclusions p-Cresol shows a preponderance of sulfate conjugation, although a relatively diminished sulfotransferase activity can be suggested in patients with advanced CKD. Along with total p-cresol burden, a relative shift from sulfate to glucuronide conjugation is independently associated with mortality and cardiovascular disease, warranting increased focus to the dynamic interplay between microbial and endogenous metabolism.

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Section: Discussionmentioning

confidence: 99%

Metabolism, Protein Binding, and Renal Clearance of Microbiota–Derived p-Cresol in Patients with CKD

Poesen

Evenepoel

Loor

et al. 2016

CJASN

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“…This is in line with the increasing recognition of the role of tubulo-interstitium in the pathophysiology of renal disease and, accordingly, the notion that an integrative measure of both glomerular and tubular function may bear more prognostic relevance than a specific measure for GFR only (42). Considering the substrate polyspecificity of OCT2 (59), reduced tubular secretion of various candidate substances might potentially be involved, including catecholamines, dopamine, prostaglandins, advanced glycation end products, and, possibly, uremic toxins, that could affect the kidney either directly or by effects on blood pressure and volume status and hence promote progressive renal damage (16,20,28,32,56,60). Finally, the association with ESRD as indicator for the susceptibility to renal damage is corroborated by recent GWAS data reporting a suggestive association between rs316019 and diabetic nephropathy (43).…”

Section: Discussionmentioning

confidence: 99%

SLC22A2is associated with tubular creatinine secretion and bias of estimated GFR in renal transplantation

Reznichenko

Sinkeler

Snieder

et al. 2013

Physiological Genomics

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-Genomewide association studies reported SLC22A2 variants to be associated with serum creatinine. As SLC22A2 encodes the organic cation transporter 2 (OCT2), the association might be due to an effect on tubular creatinine handling. To test this hypothesis we studied the association of SLC22A2 polymorphisms with phenotypes of net tubular creatinine secretion: fractional creatinine excretion (FE creat) and bias of estimated glomerular filtration rate (eGFR). We also studied the association with end-stage renal disease (ESRD) and graft failure (GF) in renal transplant recipients. SLC22A2 single nucleotide polymorphisms (SNPs), rs3127573 and rs316009, were genotyped in 1,142 ESRD patients receiving renal transplantation and 1,186 kidney donors as controls. GFR was measured with 125 I-iothalamate clearance. Creatinine clearance was also assessed. FEcreat was calculated from the simultaneous clearances of creatinine and 125 I-iothalamate. Donor rs316009 was associated with FEcreat (beta Ϫ0.053, P ϭ 0.024) and with estimated [modification of diet in renal disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)] but not measured GFR. In line with this, donor rs316009 was associated with bias of the MDRD and CKD-EPI but not the Cockroft-Gault equation. Both SNPs were associated with ESRD: odds ratios [95% CI] 1.39 [1.16 -1.67], P ϭ 0.00065, and 1.23 [1.02-1.48], P ϭ 0.042, for rs3127573 and rs316009, respectively. Neither SNP was associated with GF. Thus, SLC22A2 is associated with phenotypes of net tubular creatinine secretion and ESRD. creatinine tubular secretion; SNP; genetic polymorphism; GWAS; OCT2 GENOME-WIDE ASSOCIATION STUDIES (GWAS) identified a number of loci influencing renal function (7, 23, 24) usually using renal function estimates based on serum creatinine as a proxy for glomerular filtration rate (GFR).Serum creatinine, however, is determined not only by GFR, but also by the rate of creatinine generation, extrarenal elimination, and by tubular handling (5,31,35,46,49). Dissecting the biological mechanisms underlying genetic associations with serum creatinine, therefore, is pivotal for proper interpretation of GWAS findings. In particular, it is relevant to assess whether loci associated with serum creatinine reflect susceptibility to renal damage (1) or, alternatively, reflect biological variations in creatinine generation or in creatinine handling unrelated to the risk for renal damage.The SLC22A2 gene is associated with serum creatinine and estimated GFR (eGFR) (7). However, SLC22A2 might well be a creatinine secretion locus. First, SLC22A2 single nucleotide polymorphisms (SNPs) were associated with GFR estimated from serum creatinine but not cystatin C (23, 34). Second, the SLC22A2 gene encodes the organic cation transporter 2 (OCT2), a predominant transporter involved in tubular creatinine secretion. It is expressed in the basolateral membrane of proximal tubule cells (29), where it mediates creatinine uptake from the peritubular capillaries, as an initial step in tubular crea...

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“…Both are involved in urinary secretion of urate (36,86), a uremic toxin responsible for the pathogenesis of gout and cardiovascular disease. The interaction of the uremic retention solutes hippuric acid, indoxyl sulfate and kynurenic acid with MRP4 and BCRP, and of indole-3-acetic acid and phenylacetic acid with MRP4 only was recently demonstrated (87). The inhibition of transport by the uremic toxins occurred at clinically relevant concentrations, suggesting that this mechanism may contribute to the progression and the many complications of CKD.…”

Section: Chronic Renal Failurementioning

confidence: 99%

Regulatory Pathways for ATP-binding Cassette Transport Proteins in Kidney Proximal Tubules

Masereeuw

Rüssel

2012

AAPS J

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Abstract. The ATP-binding cassette transport proteins (ABC transporters) represent important determinants of drug excretion. Protective or excretory tissues where these transporters mediate substrate efflux include the kidney proximal tubule. Regulation of the transport proteins in this tissue requires elaborate signaling pathways, including genetic, epigenetic, nuclear receptor mediated, posttranscriptional gene regulation involving microRNAs, and non-genomic (kinases) pathways triggered by hormones and/or growth factors. This review discusses current knowledge on regulatory pathways for ABC transporters in kidney proximal tubules, with a main focus on P-glycoprotein, multidrug resistance proteins 2 and 4, and breast cancer resistance protein. Insight in these processes is of importance because variations in transporter activity due to certain (disease) conditions could lead to significant changes in drug efficacy or toxicity.

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Uremic Toxins Inhibit Transport by Breast Cancer Resistance Protein and Multidrug Resistance Protein 4 at Clinically Relevant Concentrations

Cited by 119 publications

References 35 publications

Metabolism, Protein Binding, and Renal Clearance of Microbiota–Derived p-Cresol in Patients with CKD

Metabolism, Protein Binding, and Renal Clearance of Microbiota–Derived p-Cresol in Patients with CKD

SLC22A2is associated with tubular creatinine secretion and bias of estimated GFR in renal transplantation

Regulatory Pathways for ATP-binding Cassette Transport Proteins in Kidney Proximal Tubules

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